The invention relates to devices and methods for delivering a therapeutic solution, and more specifically to a steerable needle and a method for delivering an angiogenic substance into a beating heart.
There have been numerous recent advances in therapies such as angioplasty and coronary bypass surgery, which are now commonly used in the treatment of ischemic heart disease. There still exist a significant number of patients for whom these conventional therapies are not feasible options in a number of circumstances. For example, conventional coronary bypass surgery is not a treatment option in patients with diffuse small vessel coronary artery disease due to the small size and large number of diseased vessel segments. Further, re-occlusion of a diseased vessel may occur despite multiple angioplastic procedures or bypass surgeries.
One promising alternative treatment for ischemic heart disease is the delivery of angiogenesis-promoting substances to the heart tissue to induce angiogenesis. Angiogenesis is a complex biological process that results in the growth of new blood vessels within tissue. Angiogenesis is an essential process common to several normal and pathologic conditions including embryologic development, wound healing, development of neoplasms, and the like. Angiogenesis involves the disruption of vascular basement membranes, migration and proliferation of endothelial cells, and subsequent blood vessel formation and maturation.
Angiogenesis has also been induced in heart tissue for reperfusion of tissue compromised by myocardial ischemia. Several growth factors or mediators are known to elicit angiogenic responses, and administration of these mediators promotes revascularization of ischemic tissues. These growth factors are typically proteins which stimulate endothelial cell reproduction in the target tissue. Vascular endothelial growth factor (VEGF) is one of the most specific of the known angiogenic mediators due to localization of its receptors almost exclusively on endothelial cells. Receptors for VEGF are upregulated under ischemic conditions. Accordingly, the administration of VEGF augments the development of collateral vessels and improves function in peripheral and myocardial ischemic tissue.
Delivery of VEGF remains a significant challenge. The half-life of VEGF is very short. Accordingly, the tissue must be exposed to the growth factor for a period of days. The administration of high doses of VEGF, however, is associated with hypotension.
The systemic administration of VEGF can induce angiogenesis in tissues other than that which has been targeted, such as occult tumors, or sensitive diseased organs, such as the retina. This promiscuous induction of angiogenesiscan cause blindness, increase the aggressiveness of tumor cells, and lead to a multitude of other negative side-effects. Accordingly, the growth factor should be limited to the target tissue.
The growth factor can be delivered to the target tissue through the use of indwelling catheters over a period of time. A preferred method of delivering the growth factor, however, is in the form of gene transfer, for example, by a replication deficient adenoviral vector containing the transgene coding for the growth factor. Under this method, a quantity of the adenoviral vector having the desired genetic component is delivered to the treatment area by injection in solution.
In the past, an open-chest procedure has been used to deliver the treatment solution. According to this procedure, the patient""s chest is opened surgically to expose the heart. The solution containing the adenoviral vector is then delivered to the heart tissue by using a syringe to make a number of injections in a grid-like pattern, with the surgeon keeping track of the location of each injection. International Patent Application WO 98/32859 discloses a method of enhancing the level of perfusion of blood to a target tissue during such procedure.
Once injected, the adenoviral vector causes the cells in the target tissue to produce the desired growth factor, and this growth factor production of the treated cells will continue for a period of time. Previous studies have shown the feasibility and efficacy of safe, sustained, and localized expression of angiogenesis-promoting growth factors utilizing adenoviral-mediated gene transfer therapy.
It is desirable to be able to provide the above described therapy without the necessity of performing open-chest surgery on the patient. U.S. Pat. No. 5,997,509 discloses an injection apparatus and method for providing gene therapy treatment to the heart or other internal organs without necessitating such open heart surgery. A procedure for utilizing a device also is disclosed in International Patent Application WO 99/44656. According to the procedure, the patient""s lung is partially collapsed to enable access to areas of the heart. The therapeutic substance may be injected into the patient""s myocardium by passing the needle directly through the patient""s pericardium.
The device disclosed in the ""509 patent and International Patent Application WO 99/44656 includes an elongate flexible tubular body having a hollow needle mounted at the distal end for delivery of the therapeutic substance to the tissue. This and other currently available devices have relatively complex designs, and, accordingly, are extremely expensive to manufacture. Further, they may be difficult to manipulate around the contours of the heart or to ensure stability of the needle against the target cardiac tissue.
Additionally, access to the target cardiac tissue is often obscured by other organs and tissues. One or more retractors may be used in order to physically move the obscuring organs or tissues in order to gain access to the cardiac tissue. A grasping type of retractor, a mechanically expandable retractor, an inflatable retractor, or another type of retractor known in the art may be utilized as disclosed, for example, in International Patent Application WO 99/44656. In reoperative patients, however, lung tissue frequently adheres directly to the cardiac tissue. Under these conditions, the lung and cardiac tissues cannot typically be separated by conventional methods without damage to either or both of the organs. As a result, retraction devices such as those disclosed in the ""509 patent and International Patent Application WO 99/44656 are not readily utilized under such circumstances.
The present invention provides a method and a minimally invasive injection device which is steerable such that it may be maneuvered into a desired position for administering an injection. The device includes a hollow needle which is adapted for connection to a solution supply. The needle has an elongated flexible body with a sharpened tip at its distal end for penetration into tissue. The needle may be steered by means of a steering cable and a moveable steering sleeve.
The steering cable is an elongated cable or wire which is coupled to the needle toward its distal end and extends substantially the length of the needle to its proximal end. The user may exert a tensioning force on the steering cable to cause the elongated flexible body of the needle to flex or arch along a flexion radius. The moveable steering sleeve is slideably disposed along the elongated flexible body with the steering cable extending through the steering sleeve. Accordingly, by moving the steering sleeve axially along the needle, the user can adjust the flexion radius of the needle. That is, the needle body will be substantially straight from its proximal end up to and including the section extending through the steering sleeve. As a tension force is exerted on the steering cable, however, the needle body distal the steering sleeve will flex or arch, moving the needle tip toward the proximal end of the needle. The steering sleeve may be slid along the needle by means of a sufficiently rigid steering sleeve adjustment cable, which likewise extends toward and can be operated from the proximal end of the needle. Thus, the device provides a simplified, steerable needle arrangement that may be efficiently and economically produced.
A device constructed according to teachings of the invention can be easily controlled and efficiently maneuvered within a body cavity, the flexible needle contouring to cardiac and thoracic geometry to properly position the needle tip and administer the injection. Accordingly, the device may readily be utilized in minimally invasive procedures to deliver angiogenesis-promoting substances from a remote location to an area of ischemic heart tissue without necessitating open-chest surgery.
The delivery of the therapeutic substance to the myocardium can be by way of any suitable route, transpericardially, as well as endocardially. While the device may be utilized during open-heart surgery, or advanced into the heart through any artery, including, for example, the femoral artery, the device may also be utilized in the manner disclosed in International Patent Application WO 99/44656. More specifically, the patient""s lung may be partially collapsed by the introduction of gas into the patient""s thoracic cavity. This enlarges the working area for injection of the therapeutic substance and increases access to heart tissue.
According to other features of the invention, various methods of delivering a therapeutic substance are disclosed. One such method includes the steps of inserting an elongated device body into a body cavity through an opening, and using the steering cable, and the steering sleeve adjustment cable and steering sleeve to steer the body distal end within the cavity. Another method further includes the steps of inserting the device into the patient""s thoracic cavity through an opening the patient""s chest wall, passing a needle into the heart tissue and delivering the therapeutic substance. Further, the needle may be passed directly into the chest cavity in a true percutaneous technique wherein no incision is made. Under these circumstances, the opening in the chest is limited only the diameter of the device or a small trocar.
Inasmuch as access to cardiac tissue is often limited in re-operative patients, however, the invention further includes a methods of administering the therapeutic solution when lung tissue adhering to the heart obscures access. According to the method, the needle is passed directly through the patient""s lung tissue and into the heart tissue. According to another method, the device is stabilized against the tissue by means of a moveable stabilizing platform which is disposed either against the lung tissue or against the pericardium.
According to one design, the stabilizing platform is spaced from the distal tip of the needle and can transit the needle tip a sufficient distance to allow the needle tip to penetrate and pass through the lung tissue, and to penetrate the heart tissue to a desired depth. The distal-most position of the movable platform is preferably the optimum cardiac tissue penetration depth. The movable platform may be retained on the needle tip by a stop along the needle tip, or any other appropriate structure or means. According to a preferred embodiment, the platform can transit the needle tip from a position approximately 5-10 mm from the distal tip to approximately 35-50 mm proximal the distal tip. In this way, the needle tip can penetrate and extend through the lung tissue, and then penetrate the cardiac tissue a desired depth to administer the therapeutic solution.
According to another feature of the invention, the platform may be stopped, advanced to, or disposed at a desired position to provide the optimum cardiac tissue penetration when cardiac penetration has been confirmed via an ECG signal. An electrode is preferably located on the on the distal tip of the needle, and connected to an ECG. In this way, the surgeon can determine when the needle has penetrated the patient""s myocardium and is properly positioned. Penetration of the myocardium by the needle will show as a current injury on the ECG.
By way of further example, the moveable platform may be in the form of an inflatable balloon which may be inflated to a desired volume once cardiac contact has been confirmed. Inflation may be accomplished by means of a gas line extending along the length of the needle body between the platform and an appropriate gas source. The platform of this design is preferably disposed along the needle tip at a given axial position which defines the optimum cardiac penetration depth. The deflated platform may be passed through the lung tissue and then inflated adjacent the heart tissue when proper placement has been confirmed. Other platform designs such as a spring-biased platform may be provided.